Note: Descriptions are shown in the official language in which they were submitted.
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PROCESSES FOR THE PREPARATION OF 2-THIOPHENECARBONYL CHLORIDE
FIELD
[0001] Provided herein are processes for the preparation of 2-
thiophenecarbonyl
chloride.
BACKGROUND
[0002] Acyl chlorides are useful as starting materials and reagents in the
preparation of a
wide variety of industrially useful compounds. For example, U.S. Pub. No.
2014/0039197 Al
reports that acyl chlorides can be reacted with N-hydroxyamidines in the
preparation of 3,5-
disubstituted-1,2,4-oxadiazoles, which are useful for, in part, nematode
control in agriculture.
For example, 2-thiophenecarbonyl chloride is useful in the preparation of
tioxazafen (3-phenyl-
5-(2-thieny1)-1,2,4-oxadiazole) by reaction with benzamide oxime.
[0003] While methods for preparing 2-thiophenecarbonyl chloride are known in
the art,
alternative routes that may result in a more efficient synthesis are highly
desirable.
[0004] Citation of any reference above is not to be construed as an admission
that such
reference is prior art to the present application.
SUMMARY
[0005] Provided herein are processes for the preparation of 2-
thiophenecarbonyl
chloride.
[0006] For example, in one embodiment, the process comprises reacting
thiophene with
chlorosulfonyl isocyanate in a reaction medium comprising an organic solvent,
thereby
producing (thiophene-2-carbonyl)sulfamoyl chloride, wherein the reaction is
initiated by mixing
the thiophene and the chlorosulfonyl isocyanate, and wherein the
chlorosulfonyl isocyanate is
present in molar excess relative to thiophene.
[0007] In another embodiment, the process comprises reacting thiophene with
chlorosulfonyl isocyanate in a reaction medium comprising an organic solvent,
thereby
producing (thiophene-2-carbonyl)sulfamoyl chloride, wherein the organic
solvent comprises
dibutyl ether.
[0008] In a further embodiment, the process comprises mixing a first liquid
medium
comprising thiophene dissolved in dibutyl ether and a second liquid medium
comprising
chlorosulfonyl isocyanate, thereby producing a third liquid medium comprising
(thiophene-2-
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2
carbonyl)sulfamoyl chloride in the form of a substantially homogeneous
solution or a solid
suspension in a liquid organic phase comprising dibutyl ether, wherein the
chlorosulfonyl
isocyanate is present in the second liquid medium in molar excess relative to
thiophene in the
first liquid medium; adding at least a portion of the third liquid medium to
an aqueous medium
comprising hydrochloric acid or sulfuric acid, thereby producing a fourth
liquid medium
comprising 2-thiophenecarboxylic acid dissolved in an organic phase comprising
dibutyl ether;
and reacting at least a portion of the 2-thiophenecarboxylic acid present in
the fourth liquid
medium with thionyl chloride, thereby producing a reaction medium comprising 2-
thiophenecarbonyl chloride.
[0009] In a further embodiment, the process comprises mixing a first liquid
medium
comprising thiophene dissolved in dibutyl ether and a second liquid medium
comprising
chlorosulfonyl isocyanate, thereby producing a third liquid medium comprising
(thiophene-2-
carbonyl)sulfamoyl chloride in the form of a substantially homogeneous
solution or a solid
suspension in a liquid organic phase comprising dibutyl ether, wherein the
chlorosulfonyl
isocyanate is present in the second liquid medium in molar excess relative to
thiophene in the
first liquid medium; adding at least a portion of the third liquid medium to
an aqueous medium
comprising sodium hydroxide or potassium hydroxide, thereby producing a fourth
liquid
medium comprising a salt form of 2-thiophenecarboxylic acid in an organic
phase comprising
dibutyl ether; neutralizing at least a portion of the fourth liquid medium to
a fifth liquid medium
comprising 2-thiophenecarboxylic acid dissolved in an organic phase comprising
dibutyl ether;
and reacting at least a portion of the 2-thiophenecarboxylic acid present in
the fifth liquid
medium with thionyl chloride, thereby producing a reaction medium comprising 2-
thiophenecarbonyl chloride.
[0010] In a further embodiment, the process comprises mixing a first liquid
medium
comprising thiophene dissolved in dibutyl ether and a second liquid medium
comprising
chlorosulfonyl isocyanate, thereby producing a third liquid medium comprising
(thiophene-2-
carbonyl)sulfamoyl chloride in the form of a substantially homogeneous
solution or a solid
suspension in a liquid organic phase comprising dibutyl ether, wherein the
chlorosulfonyl
isocyanate is present in the second liquid medium in molar excess relative to
thiophene in the
first liquid medium; adding at least a portion of the third liquid medium to
an aqueous medium
comprising water, thereby producing a fourth liquid medium comprising 2-
thiophenecarboxamide; contacting at least a portion of the forth liquid medium
in the presence
of a strong acid or a strong base, thereby producing a fifth liquid medium of
2-
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thiophenecarboxylic acid in an organic phase comprising dibutyl ether; and
reacting at least a
portion of the 2-thiophenecarboxylic acid present in the fifth liquid medium
with thionyl
chloride, thereby producing a reaction medium comprising 2-thiophenecarbonyl
chloride.
[0011] In a further embodiment, the process is directed to the preparation of
a 3,5-
disubstituted 1,2,4-oxadiazole of Formula (I) or a salt thereof,
0
Ar2
Ari
(I)
and comprises adding a first liquid medium comprising thiophene dissolved in
dibutyl ether to a
second liquid medium comprising chlorosulfonyl isocyanate, thereby producing a
third liquid
medium comprising (thiophene-2-carbonyl)sulfamoyl chloride in the form of a
substantially
homogeneous solution or a solid suspension in a liquid organic phase
comprising dibutyl ether,
wherein the chlorosulfonyl isocyanate is present in the second liquid medium
in molar excess
relative to thiophene in the first liquid medium; adding at least a portion of
the third liquid
medium to an aqueous medium comprising a strong acid or a strong base, thereby
producing a
fourth liquid medium comprising 2-thiophenecarboxylic acid dissolved in an
organic phase
comprising dibutyl ether; reacting at least a portion of the 2-
thiophenecarboxylic acid present in
the fourth liquid medium with thionyl chloride, thereby producing a reaction
medium
comprising 2-thiophenecarbonyl chloride; and reacting at least a portion of
the 2-
thiophenecarbonyl chloride obtained in the fourth liquid reaction medium with
an N-
hydroxyamidine of Formula (II), or a tautomeric form thereof,
Arl NH
HN
OH
(II)
wherein Ari is selected from the group consisting of phenyl, pyridyl, pyrazyl,
oxazolyl or
isoxazolyl, each of which can be optionally independently substituted with one
or more
substituents selected from the group consisting of halogen, CF3, CH3, OCF3,
OCH3, CN and
C(H)0, and Ar2 is thienyl, which can be optionally independently substituted
with one or more
substituents selected from the group consisting of fluorine, chlorine, CH3,
and OCF3.
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DETAILED DESCRIPTION
[0012] Generally, the present disclosure is directed to improved processes for
the
preparation of 2-thiophenecarb onyl chloride.
ci
2-thiophenecarbonyl chloride
(TCC)
[0013] Various embodiments of the process enable greater ease of production,
milder
reaction conditions, reduced reaction time cycles, fewer reaction
intermediates, and/or
significantly reduced capital equipment requirements.
[0014] Solvents
[0015] Each of the process steps described herein in the preparation 2-
thiophenecarbonyl
chloride may be conducted in a reaction medium comprising an organic solvent.
Solvents used
to form the reaction medium may be selected on the basis of one or more
criteria to facilitate
simplification and overall economics of the process. In general, the process
steps described
herein can be conducted utilizing batch, semibatch, or continuous reactor
designs.
[0016] As disclosed herein, in one embodiment, the solvent may be selected so
that each
of the process steps can be carried out in a reaction medium comprising the
selected solvent. The
use of a single-solvent synthesis process provides a number of significant
benefits. Processes
with fewer isolation steps and/or solvents typically are more efficient, are
less expensive to
operate, and can significantly reduce capital equipment expenditures required
for large scale
manufacturing operations. In one embodiment of the process described herein, a
particular
advantage is that it is not necessary to isolate the product of each reaction
step for use in a
subsequent step¨the entire organic solvent phase can be transferred from one
step to the next
without need for purification or isolation of the intermediate reaction
products. This can be
particularly advantageous in the case of hydrolytically unstable
intermediates. In other
embodiments, the solvent in the reaction medium may be exchanged between one
or more of the
process steps, wherein suitable solvents are selected independently from each
other.
[0017] In one embodiment, the organic solvent may form an azeotrope with
water. The
formation of an azeotrope facilitates removal, via e.g. evaporation or
distillation, of the water in
the 2-thiophenecarboxylic acid intermediate to substantially anhydrous
conditions for effective
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use of the chlorinating reagent during subsequent conversion to the 2-
thiophenecarbonyl
chloride product.
[0018] In various embodiments, the solvent exhibits a boiling point that
facilitates
separation of the solvent from the 2-thiophenecarbonyl chloride product during
distillation; does
not exhibit significant reactivity in the presence of any reagent,
intermediate species or
byproducts described herein; or is stable in the presence of strong acids used
in the hydrolysis
step described herein.
[0019] Non-limiting examples of organic solvents suitable for use in
connection with the
process described herein include C1-C10 alkane solvents, Ci-Cio halogenated
alkane solvents, C1-
Cio alkylbenzenes, halogenated aromatic solvents, dialkyl ether solvents of
the general formula
R¨O¨R', wherein R and R' are each independently selected from Cl-C6 alkyl, and
ester solvents
of the formula R¨C(0)0¨R' wherein R and R' are each independently selected
from C1-C6 alkyl.
[0020] In some embodiments, the organic solvent comprises a Ci-Cio alkane
compound.
The compound may comprise one or more C1-C10 linear, branched or cyclic alkyl
groups. By
way of non-limiting example, the organic solvent may comprise hexane, 2-
methylhexane, or
cyclohexane.
[0021] In some embodiments, the organic solvent comprises a C1-C10 halogenated
alkane
solvent. The compound may comprise one or more Ci-Cio linear, branched or
cyclic alkyl
groups. In some embodiments, the compound may comprise one or more halogen
substituents
independently selected from F, Cl, and Br. For example, the compound may
comprise from one
to six halogen substituents. By way of non-limiting example, the organic
solvent may comprise
dichloromethane, dichloroethane, chloroform, or carbon tetrachloride.
[0022] In some embodiments, the organic solvent comprises a Ci-Cio
alkylbenzene
compound. The compound may comprise one or more C1-C10 linear, branched or
cyclic alkyl
groups, each of which may be optionally independently substituted with one or
more halogen
substituents independently selected from F, Cl, and Br. For example, the
compound may
comprise from one to six halogen substituents. In some embodiments, the alkyl
groups are
saturated alkyl groups. By way of non-limiting example, the organic solvent
may comprise
toluene, o-xylene, p-xylene, m-xylene, xylenes, trimethylbenzene, or
trifluorotoluene.
[0023] In some embodiments, the organic solvent comprises a halogenated
aromatic
compound comprising one or more halogen substituents independently selected
from F, Cl, and
Br. For example, the compound may comprise from one to six halogen
substituents. By way of
non-limiting example, the organic solvent may comprise chlorobenzene,
dichlorobenzene,
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chlorotoluene, or hexafluorobenzene.
[0024] In some embodiments, the organic solvent comprises a compound of the
formula
R¨O¨R' wherein R is selected from C4-C6 cycloalkyl and R' is methyl. For
example, the organic
solvent may comprise cyclopentyl methyl ether.
[0025] In other embodiments, the organic solvent comprises a compound of the
formula
R¨O¨R' wherein R and R' are each C3-C6 alkyl. For example, the organic solvent
may comprise
dibutyl ether. In such embodiments, dibutyl ether forms peroxides at a much
slower rate as
compared to other ethereal solvents.
[0026] In further embodiments, steps other than the hydrolysis step described
herein may
be conducted in the presence of an organic solvent comprising an ester
compound of the formula
R¨C(0)0¨R' wherein R and R' are each independently selected from Ci-C6 alkyl.
For example,
the organic solvent may comprise ethyl acetate, isopropyl acetate, butyl
acetate, or isobutyl
acetate.
[0027] Conversion of thiophene to (thiophene-2-carbonyl)sulfamoyl chloride
[0028] In various embodiments, the processes disclosed herein comprise a step
wherein
thiophene is reacted with chlorosulfonyl isocyanate (CSI) to produce
(thiophene-2-
carbonyl)sulfamoyl chloride (NC SAT).
[0029] In one embodiment, it has been observed that the chlorosulfonyl
isocyanate reacts
almost exclusively with the 2-position carbon of the thiophene ring. Other
methods of thiophene
substitution known in the art produce significant amounts of the 3-position
isomer. In some
embodiments, the reaction described herein can be used to produce (thiophene-2-
carbonyl)sulfamoyl chloride in a molar ratio of at least about 99:1 in
relation to the (thiophene-
3-carbonyl)sulfamoyl chloride isomer.
[0030] Without being bound to a particular theory, in some embodiments, the
reaction of
thiophene and chlorosulfonyl isocyanate is believed to form N-(thiophen-2-
ylsulfonyl)thiophene-2-carboxamide (NTSAT) as a byproduct. To minimize the
formation of
reaction byproducts, the reaction may be carried out with chlorosulfonyl
isocyanate present in
molar excess relative to thiophene. For example, the molar ratio of
chlorosulfonyl isocyanate to
thiophene, in terms of the amount of each reactant added to the reaction
medium, may be greater
than about1.05:1, greater than about 1.1:1, greater than about 1.15:1, greater
than about 1.2:1, or
greater than about 1.25:1. In some embodiments, the molar ratio of
chlorosulfonyl isocyanate to
thiophene may be from about 1.05:1 to about 1.5:1, from about 1.05:1 to about
1.25:1, from
about 1.05:1 to about 1.2:1, from about 1.05:1 to about 1.15:1, from about
1.1:1 to about 1.5:1,
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from about 1.1:1 to about 1.25:1, from about 1.1:1 to about 1.2:1, or from
about 1.1:1 to about
1.15:1.
[0031] The reactants may be combined using a conventional order of addition,
wherein
the chlorosulfonyl isocyanate is added to thiophene. In certain embodiments,
however, the
reactants are combined using reverse addition, wherein the thiophene is added
to chlorosulfonyl
isocyanate. In some embodiments, the addition of thiophene to chlorosulfonyl
isocyanate results
in generation of fewer reaction byproducts and increases the yield of
(thiophene-2-
carbonyl)sulfamoyl chloride. In some embodiments, reverse addition of
thiophene to
chlorosulfonyl isocyanate, under conditions where chlorosulfonyl isocyanate is
constantly
present in molar excess during the reaction as described above, may promote
conversion of
thiophene to (thiophene-2-carbonyl)sulfamoyl chloride and minimize the
production of NTSAT.
[0032] The reaction of thiophene with chlorosulfonyl isocyanate produces the
reaction
product (thiophene-2-carbonyl)sulfamoyl chloride, which may be present as a
substantially
homogenous solution in the organic solvent, as a solid suspension, or as a
slurry in the organic
solvent. In one embodiment, the reaction produces a substantially homogeneous
reaction
mixture in the organic solvent and thereafter the (thiophene-2-
carbonyl)sulfamoyl chloride
reaction product is retained as a solute in the organic solvent during and/or
after the reaction. In
some embodiments, the (thiophene-2-carbonyl)sulfamoyl chloride is not isolated
from the
homogenous reaction medium. In other embodiments, the (thiophene-2-
carbonyl)sulfamoyl
chloride is isolated from the homogenous reaction medium by distillation of
the organic solvent
or extraction. In another embodiment, the reaction initially produces a
substantially
homogeneous reaction mixture and thereafter the (thiophene-2-
carbonyl)sulfamoyl chloride
reaction product forms a solid precipitate. In some embodiments, when the
reaction is
substantially complete, the (thiophene-2-carbonyl)sulfamoyl chloride is
retained in the reaction
medium as a solid suspension or slurry in the organic solvent, and is not
filtered or otherwise
isolated from the reaction medium. In other embodiments, the solid suspension
or slurry of the
(thiophene-2-carbonyl)sulfamoyl chloride is isolated from the organic solvent
by filtration,
centrifugation, and/or decanting.
[0033] In some embodiments, the addition of chlorosulfonyl isocyanate to
thiophene or
the reverse addition of thiophene to chlorosulfonyl isocyanate as described
herein may result in a
solid precipitate that comprises greater than about 90 area% purity of
(thiophene-2-
carbonyl)sulfamoyl chloride as measured by a reverse phase high-performance
liquid
chromatography (RP-HPLC) method. In some embodiments, the solid precipitate
may comprise
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greater than about 95 area%, greater than about 96 area%, greater than about
97 area%, greater
than about 98 area%, or greater than about 99 area% purity of (thiophene-2-
carbonyl)sulfamoyl
chloride as measured by a RP-HPLC method.
[0034] In some embodiments, the reaction of thiophene with chlorosulfonyl
isocyanate is
carried out at a temperature of from about -20 C to about 100 C, from about -
20 C to about
0 C, from about 0 C to about 50 C, from about 35 C to about 50 C, or from
about 50 C to
about 100 C.
[0035] Conversion of (thiophene-2-carbonyl)sulfamoyl chloride to 2-
thiophenecarboxylic acid
[0036] In various embodiments, the processes disclosed herein further comprise
a step
wherein (thiophene-2-carbonyl)sulfamoyl chloride is hydrolyzed to produce 2-
thiophenecarboxylic acid.
[0037] In some embodiments, the hydrolysis reaction is conducted in the
presence of an
acidic aqueous medium. For example, the acidic aqueous medium may comprise a
strong acid,
defined herein as an acid that completely or almost completely dissociates in
water. Non-
limiting examples of suitable acids include mineral acids such as hydrochloric
acid and sulfuric
acid. In some embodiments, the concentration of hydrochloric acid in the
aqueous solution is
from about 1 M to about 12 M, or from about 3 percent by weight (wt%) to about
37 wt%. In
other embodiments, the concentration of sulfuric acid in the aqueous solution
is from about 1 M
to about 18 M, or from 5 wt% to about 95 wt%.
[0038] In some embodiments, (thiophene-2-carbonyl)sulfamoyl chloride, present
in the
form of homogenous solution, a suspension or slurry in the organic solvent as
described herein,
is added to the acidic aqueous medium. In other embodiments, (thiophene-2-
carbonyl)sulfamoyl
chloride, present in the form of isolated solids as described herein, is added
to an acidic aqueous
medium and additional organic solvent (e.g., dibutyl ether) is added to the
resulting reaction
medium. In some embodiments, the resulting reaction medium is biphasic at or
near room
temperature, but can become substantially homogeneous at or above a
temperature of about
100 C.
[0039] In some embodiments, the volumetric ratio of the organic solvent to the
aqueous
acidic medium is from about 3:4 to about 1:1. In other embodiments, the
volumetric ratio of the
organic solvent to the aqueous acidic medium is from about 1:2 to about 1:1,
from about 2:3 to
about 1:1, or from about 1:4 to about 1:1.
[0040] Because the reaction is exothermic, the acidic aqueous medium may be
chilled to
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below ambient temperature prior to combination with the (thiophene-2-
carbonyl)sulfamoyl
chloride suspension, slurry, or isolated solid in order to control the
exotherm. For example, the
acidic aqueous medium may be chilled to a temperature of from about 0 C to
about 10 C. In
some embodiments, during the initial exothermic reaction, the temperature of
the reaction
medium is maintained at a temperature below about 50 C, for example from about
30 C to
about 50 C. Rapidly stirring the acidic aqueous medium before and/or during
the reaction may
also be helpful to control the exotherm and maintain a consistent temperature
throughout the
reaction medium. In some embodiments, the temperature of the reaction medium
during the
hydrolysis reaction, wherein the organic solvent (e.g., dibutyl ether) is
raised to a temperature of
at least about 50 C. For example, in some embodiments, the temperature is
maintained at from
about 50 C to about 130 C, from about 70 C to about 115 C, from about 90 C to
about 110 C,
or at least about 80 C.
[0041] In some embodiments, the hydrolysis reaction is conducted in the
presence of a
basic aqueous medium. For example, the basic aqueous medium may comprise a
strong base,
defined herein as a base that completely or almost completely dissociates in
water. Non-limiting
examples of suitable bases include alkali or alkaline earth hydroxides such as
sodium hydroxide,
potassium hydroxide and mixtures thereof. In some embodiments, the
concentration of sodium
hydroxide in the aqueous solution is from about 1 M to about 20 M, or from
about 2.5 wt% to
about 50 wt%. In other embodiments, the concentration of potassium hydroxide
in the aqueous
solution is from about 1 M to about 12 M, or from 4 wt% to about 45 wt%. A
neutralization step
is conducted to convert a salt form of 2-thiophenecarboxylic acid from the
base hydrolysis with
an acid to the 2-thiophenecarboxylic acid.
[0042] In some embodiments, the hydrolysis reaction is conducted initially in
the
presence of an aqueous medium to form 2-thiophenecarboxamide (TCAm) as an
intermediate,
wherein the aqueous medium comprises water. The intermediate 2-
thiophenecarboxamide
(TCAm) is further hydrolyzed in the presence of an acidic aqueous medium or a
basic aqueous
medium. The acidic aqueous medium may comprise a strong acid and the basic
aqueous medium
may comprise a strong base, as defined above. In some embodiments, the
hydrolysis reaction is
initiated by contacting water to form 2-thiophenecarboxamide (TCAm) and
further hydrolyzed
in the presence of a strong acid selected from the group consist of
hydrochloric acid and sulfuric
acid. In some embodiments, the concentration of hydrochloric acid in the
aqueous solution is
from about 1 M to about 12 M, or from about 3 wt% to about 37 wt%. In other
embodiments,
the concentration of sulfuric acid in the aqueous solution is from about 1 M
to about 18 M, or
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from 5 wt% to about 95 wt%. In some other embodiments, the hydrolysis reaction
is initiated by
contacting water to form 2-thiophenecarboxamide (TCAm) and further hydrolyzed
in the
presence of a strong base selected from the group consist of sodium hydroxide,
potassium
hydroxide and mixtures thereof. In some embodiments, the concentration of
sodium hydroxide
in the aqueous solution is from about 1 M to about 20 M, or from about 2.5 wt%
to about 50
wt%. In other embodiments, the concentration of potassium hydroxide in the
aqueous solution is
from about 1 M to about 12 M, or from 4 wt% to about 45 wt%.
[0043] Without being bound to a particular theory, in some embodiments, the
reaction of
the (thiophene-2-carbonyl)sulfamoyl chloride and the acidic medium is believed
to form 2-
thiophenecarboxamide (TCAm) as an intermediate. It is important to achieve
complete or
substantially complete hydrolysis of 2-thiophenecarboxamide to avoid the
formation of
undesirable byproducts such as 2-thiophenecarbonitrile in subsequent process
steps. In some
embodiments, wherein the acid in the hydrolysis reaction comprises
hydrochloric acid or
sulfuric acid, the substantially complete hydrolysis of 2-thiophenecarboxamide
may be
advantageously attained.
[0044] In some embodiments, once the reaction is substantially complete, the
reaction
medium separates into an organic phase comprising the 2-thiophenecarboxylic
acid reaction
product and an aqueous phase. The organic phase can then be separated using
means known in
the art, for example by decantation. In some embodiments, additional organic
solvent is used to
extract the 2-thiophenecarboxylic acid partially remaining in the aqueous
phase to achieve more
recovery of the product.
[0045] In some embodiments, the 2-thiophenecarboxylic acid reaction product
remains
soluble in the organic phase so long as the temperature of the organic phase
is maintained
sufficiently high (e.g., at temperatures at or above about 60 C in some of the
solvents as
described herein). Accordingly, once the reaction is substantially complete,
the organic phase is
typically maintained at a temperature sufficiently high to prevent undesired
precipitation of the
2-thiophenecarboxylic acid prior to separation of the organic phase.
[0046] Conversion of 2-thiophenecarboxylic acid to 2-thiophenecarbonyl
chloride
[0047] In various embodiments, the processes disclosed herein further comprise
a
chlorination step wherein 2-thiophenecarboxylic acid is reacted with a
chlorinating reagent to
produce the 2-thiophenecarbonyl chloride product. Non-limiting examples of
chlorinating agents
include thionyl chloride, oxalyl chloride, POC13, PC15, phosgene, and other
chlorinating agents
known in the art. For example, in some embodiments, the chlorinating agent is
thionyl chloride.
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[0048] The 2-thiophenecarboxylic acid may be present in the form of a solute
in the
organic solvent as described herein. In some embodiments, the thionyl chloride
is added to a
liquid reaction medium comprising the 2-thiophenecarboxylic acid dissolved in
the organic
solvent. In some embodiments, the reaction mixture is initially heterogeneous
or multi-phasic,
but becomes substantially homogeneous or monophasic after a sufficient portion
of the
chlorinating reagent has been added.
[0049] In some embodiments, the reaction may be carried out in the presence of
a
catalyst that promotes the formation of the 2-thiophenecarbonyl chloride
product. Non-limiting
examples of catalysts include amides, imides, amines, quaternary ammonium
salts and ureas.
For example, in some embodiments, the reaction medium may comprise an N,N-
disubstituted
amide such as N,N-dimethyl formamide or N-methylpyrrolidone; a N-
monosubstituted amide
such as N-methyl formamide or N-methylacetamide; a tertiary amine such as
pyridine or
triethylamine; a secondary amine such as pyrrolidine or diethylamine; and/or a
substituted urea
such as tetramethyl urea. For example, in some embodiments, the reaction
medium comprises a
catalytic amount of N,N-dimethylformamide, wherein the molar percentage of N,N-
dimethylformamide to 2-thiophenecarboxylic acid is from about 1 mol% to about
5 mol%.
[0050] To maximize the conversion of 2-thiophenecarboxylic acid to 2-
thiophenecarbonyl chloride, the reaction may be carried out with the
chlorinating reagent present
in molar excess relative to 2-thiophenecarboxylic acid. In some embodiments,
the molar ratio of
chlorinating reagent to 2-thiophenecarboxylic acid, in terms of the amount of
each reactant
added to the reaction medium, is less than about 2:1. For example, in some
embodiments, the
molar ratio of of chlorinating reagent to 2-thiophenecarboxylic acid, in terms
of the amount of
each reactant added to the reaction medium, is from about 1:1 to about 2:1,
from about 1.5:1 to
about 2:1, from about 1.1:1 to about 1.5:1, or from about 1.1:1 to about
1.25:1.
[0051] Without being bound to a particular theory, in some embodiments wherein
the
chlorinating reagent comprises thionyl chloride, the thionyl chloride may
react with 2-
thiophenecarboxamide present along with 2-thiophenecarboxylic acid in the
reaction medium
from the hydrolysis step to form 2-thiophenecarbonitrile as a byproduct. As
noted above, the
formation of 2-thiophenecarbonitrile can be minimized by ensuring that
substantially all 2-
thiophenecarboxamide produced in the hydrolysis step has been hydrolyzed to
form 2-
thiophenecarboxylic acid before initiating the reaction with thionyl chloride.
[0052] In some embodiments, the reaction of 2-thiophenecarboxylic acid with
the
chlorinating agent is carried out at a temperature below the boiling point of
the organic solvent
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present in the reaction medium. In some embodiments, the reaction of 2-
thiophenecarboxylic
acid with the chlorinating reagent is carried out at a temperature of from
about 50 C to about
80 C, or from about 60 C to about 70 C.
[0053] Recovery of 2-thiophenecarbonyl chloride
[0054] In various embodiments, the processes disclosed herein further comprise
a step
wherein the 2-thiophenecarbonyl chloride product is recovered by distillation
of the liquid
medium.
[0055] In one embodiment, if the 2-thiophenecarbonyl chloride is produced by
reacting
2-thiophenecarboxylic acid with thionyl chloride as described above, it is
preferable to ensure
that the HC1 and SO2 gas products of the chlorination reaction have fully
evolved from the liquid
medium before starting the distillation process. In another embodiment, the
reaction medium is
maintained at a temperature from about 40 C to about 60 C and placed under
vacuum for a time
sufficient to ensure that the gas products of the chlorination reaction are
substantially removed
from the liquid medium.
[0056] Separation of the organic solvent and the 2-thiophenecarbonyl chloride
product
may be carried out using methods known in the art, including but not limited
to simple
distillation or fractional distillation. An initial distillation stage may be
operated to remove and
recover the solvent. Suitable distillation temperature and pressure conditions
for the removal and
recovery of the organic solvent will be apparent to those skilled in the art.
In some
embodiments, wherein the solvent comprises dibutyl ether, the initial
distillation is conducted at
a bath temperature of about 100 C to about 110 C under vacuum (e.g., about 30
mmHg; 4 kPa).
[0057] Recovery of the 2-thiophenecarbonyl chloride product may then be
achieved by
purification methods known in the art. For example, in some embodiments, the
remaining liquid
medium is distilled using vacuum or fractional distillation. In some
embodiments, the 2-
thiophenecarbonyl chloride product is recovered by distilling the remaining
liquid medium
under high vacuum. Suitable distillation temperature and pressure conditions
for the recovery of
the 2-thiophenecarbonyl chloride product will be apparent to those skilled in
the art.
[0058] Production of 3,5-disubstituted 1,2,4-oxadiazoles
[0059] In various embodiments, the process may further comprise steps for
producing a
3,5-disubstituted 1,2,4-oxadiazole or a salt thereof Methods for the
preparation of 3,5-
disubstituted-1,2,4-oxadiazoles that utilize acyl chlorides as a starting
material are disclosed in
U.S. Pub. No. 2014/0039197 Al, the entire contents of which are herein
incorporated by
reference.
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[0060] The following examples are to be considered as merely illustrative, and
are not
intended to limit the scope of this disclosure.
Example 1: Analytical Methods
[0061] A. Reverse-Phase High-Performance Liquid Chromatography (RP-HPLC)
Method
[0062] RP-HPLC analysis used to monitor reactions was conducted on an Agilent
1260
Infinity Analytical-Scale LC/MS Purification System equipped with a diode
array UV detector
and monitored at 230nm and 280 nm.
[0063] B. Nuclear Magnetic Resonance Method
[0064] Nuclear magnetic resonance analysis was run on a Bruker 600 MHz
instrument.
Deuterated solvents from Cambridge Isotope Laboratories, Ltd., including
methanol-d4,
chloroform-d, and dimethylsulfoxide-d6, were used as required.
[0065] C. Gas Chromatography Flame Ionization Detection (GC-FID) Method
[0066] Gas Chromatography Flame Ionization Detection (GC-FID) analysis was
used to
determine the purity and impurity profiles of thiophene-2-carbonyl chloride.
Thiophene-2-
carbonyl chloride samples were diluted in hexane and analyzed on an Agilent
7890B GC-FID
system with Agilent 7693 autosampler.
Example 2: Preparation of (Thiophene-2-carbonyl)sulfamoyl Chloride From
Thiophene
CSI (- 1.05 eq.), Bu20
cL(SNõCl
S=
35-50 C ()/
thiophene (thiophene-2-carbonyl)sulfamoyl
chloride
(NCSAT)
[0067] A. Addition by Adding Chlorosulfonyl Isocyanate (CSI) to Thiophene
[0068] A portion of CSI (7.6 mL) was added at once into a solution of
thiophene (21.0 g,
0.25 mol) in dibutyl ether (Bu20) (30 mL), and the reaction temperature
increased from room
temperature to 30 C. Additional CSI (15.2 mL) was added portion-wise (1 mL
every 5 minutes)
during which the internal temperature increased from 35 C to 50 C and was kept
below 50 C by
cooling with a water-bath. After completion of addition, the resulting mixture
was stirred at
50 C for additional one hour. The reaction mixture was homogenous initially
and became
heterogeneous with solid precipitations after an approximate 2/3 portion of
total CSI was added.
The resulting precipitate was filtered. The filtered solids were washed with
toluene and dried
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under vacuum to afford the title compound as a white solid (41 g, 75%). RP-
HPLC and IENMR
(600 MHz, chloroform-0 confirmed that the obtained material was (thiophene-2-
carbonyl)sulfamoyl chloride with a purity of 92%. 11-1-NMR (600 MHz,
chloroform-d) 6 9.4-9.3
(br s, 1H), 7.8 (m, 1H), 7.75 (m, 1H), 7.22 (m, 1H).
[0069] B. Reverse Addition by Adding Thiophene to Chlorosulfonyl Isocyanate
(CSI)
[0070] A solution of thiophene (5.0 g, 0.06 mol) in dibutyl ether (5 mL) was
added
dropwise via a dropping funnel into a solution of CSI (8.7 g, 1.03 eq.) in
dibutyl ether (10 mL)
over 45 minutes, during which the reaction temperature increased from room
temperature to
27 C. After completion of addition, the resulting mixture was warmed up to 48
C and stirred for
1.5 hours. The resulting mixture was taken directly for acid hydrolysis using
aqueous sulfuric
acid (20%).
[0071] The mixture was added into aqueous sulfuric acid (20%, 20 mL) while
keeping
the reaction flask in an ice-bath due to an exothermic reaction. After
completion of the addition,
the reaction mixture was heated at 110 C for 3 hours. After being cooled to 60
C, the layers
were separated. The aqueous layer was extracted with dibutyl ether (1 x 10
mL), and the
combined organic layers were concentrated in vacuo to afford 2-
thiophenecarboxylic acid as a
white solid (4.0 g, 53%).
[0072] C. Impurity Comparison of Two Addition Methods
[0073] The impurity profiles of two addition methods used to form (thiophene-2-
carbonyl)sulfamoyl chloride (NC SAT) from thiophene were compared. The side
product as N-
(thiophen-2-ylsulfonyl)thiophene-2-carboxamide (NTSAT) was observed to be less
than about 4
area% when the reverse addition method was used. Addition of CSI to thiophene
is very
selective (>99:1) at the 2-position of thiophene for both addition methods.
The results of these
two addition methods are provided in Table 2.
Table 2: Purity Profile of NCSAT by HPLC via Two Addition Methods
Addition Method Purity of NCSAT Impurity NTSAT Selectivity
(Area% by HPLC)) (Area% by HPLC) at 2-position (%)
Addition 92 8 >99
(CSI to thiophene)
Reverse Addition 96 4 >99
(Thiophene to CSI)
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Example 3: Hydrolysis of (Thiophene-2-carbonyl)sulfamoyl Chloride to form 2-
Thiophenecarboxylic Acid
9% aq. HC1
H -or-
NõCl 20% aq. H2SO4 OH
SS =
sT
0 / 0
105-115 C
(thiophene-2-carbonyl)sulfamoyl chloride 2-thiophenecarboxylic acid
(NCSAT) (TCA)
NH2
0
2-thiophenecarboxamide
(TCAm)
[0074] A. Hydrolysis using Aqueous Sulfuric Acid (20%)
[0075] (Thiophene-2-carbonyl)sulfamoyl chloride (10.0 g, 0.044 mol), prepared
by
Example 2-A, was suspended in a mixture of aqueous sulfuric acid (20%, 40 mL)
and dibutyl
ether (10 mL). The reaction mixture was kept below 40 C with a water-bath due
to an initial
exothermic reaction. After the initial exothermic reaction, the reaction
mixture was heated at
110 C for 2 hours. The reaction mixture became homogenous once the internal
temperature
reached 90 C. After being cooled to 75 C, the layers were separated. The
aqueous layer was
extracted with dibutyl ether (2 x 10 mL), and the combined organic layers were
concentrated in
vacuo to afford 2-thiophenecarboxylic acid as a white solid (5.2 g, 91%). RP-
HPLC and 11-1
NMR (600 MHz, DMSO-d6) confirmed that the obtained material was 2-
thiophenecarboxylic
acid acid with a purity of 97 area%. (600 MHz, DMSO-d6) 6 12-11 (br s, 1H),
7.87
(m, 1H), 7.74 (m, 1H), 7.18 (m, 1H); ESI-MS m/z 128.9 (M+H).
[0076] B. Hydrolysis using Aqueous Hydrochloric Acid (3 M, 9%)
[0077] (Thiophene-2-carbonyl)sulfamoyl chloride (10.0 g, 0.044 mol), prepared
by
Example 2-A, was suspended in aqueous hydrochloride acid (3 M, 40 mL). Dibutyl
ether (10
mL) was added to the mixture and the resulting reaction mixture was heated to
reflux. The
reaction mixture became homogenous once the internal temperature reached 90 C.
After heating
for 7 hours, the RP-HPLC showed that 2-thiophenecarboxamide (TCAm), as the
hydrolysis
intermediate, was detected to be < 0.1 area%. After being cooled to 75 C, the
layers were
separated. The aqueous layer was extracted with dibutyl ether (2 x 10 mL), and
the combined
organic layers were concentrated in vacuo to afford 2-thiophenecarboxylic acid
as a white solid
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(5.5 g, 97%). The RP-HPLC indicated that the isolated 2-thiophenecarboxylic
acid had a purity
of 99 area%.
[0078] C. Impurity Comparison of Two Hydrolysis Methods
[0079] The impurity profiles of two hydrolysis methods used to form 2-
thiophenecarboxylic acid (TCA) from (thiophene-2-carbonyl)sulfamoyl chloride
(NC SAT) were
compared. 2-thiophenecarboxamide (TCAm), an incomplete hydrolysis side
product, was
converted into 2-thiophenecarbonitrile during the next acetylation step with
thionyl chloride. 2-
thiophenecarbonitrile was an undesirable impurity in the final 2-
thiophenecarbonyl chloride
product, therefore it was important to minimize 2-thiophenecarboxamide (TCAm)
during the
hydrolysis. Hydrolysis using aqueous hydrochloride acid (3 M) was observed to
produce 2-
thiophenecarboxamide (TCAm) that was less than about 0.1 area%. The previous
impurity N-
(thiophen-2-ylsulfonyl)thiophene-2-carboxamide (NTSAT) remained in the product
TCA since
it is not hydrolyzed. The results of these two hydrolysis methods are provided
in Table 3.
Table 3: Purity Profile of TCA by HPLC via Two Hydrolysis Methods
Hydrolysis Method Purity of TCA Impurity TCAm
NTSAT
(Area% by HPLC) (Area% by HPLC)
aqueous sulfuric acid (20%) 95 2.8 Remain
aqueous hydrochloride acid (3 M) 97 <0.1
Remain
Example 4: Conversion of 2-Thiophenecarboxylic Acid to 2-Thiophenecarbonyl
Chloride
SOCl2, Bu20
or OH DMF (cat) (-C1
0 0
65 C
2-thiophenecarboxylic acid 2-thiophenecarbonyl chloride
(TCA) (TCC)
[0080] 2-thiophenecarboxylic acid (7.1 g, 0.055 mol), prepared by Example 3-A,
was
suspended in dibutyl ether (25 mL). A catalytic amount of dimethylformamide
(DMF) (0.2 mL,
0.05 eq.) was added followed by a slow addition of thionyl chloride (50C12)
(4.4 mL, 1.1 eq.).
During the addition, gases such as sulfur dioxide (SO2) and hydrogen chloride
(HC1) were
released. The resulting mixture was heated at 65 C for 1 hour after completion
of the addition,
followed by cooling to ambient temperature. Vacuum distillation (short path,
25 mmHg) gave
dibutyl ether (¨ 22 mL), which was distilled from the mixture at a vapor
temperature of 80 C
while the bath temperature was at 100 C. The remaining mixture was cooled to
room
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temperature and switched to a higher vacuum. Distillation (short path, 2 mmHg)
at a vapor
temperature of 40 C (bath temperature was at 60 C) afforded 2-
thiophenecarbonyl chloride as a
clear oil (6.0 g, 74%). GC-FID and 1-1-1NMR (600 MHz, chloroform-0 confirmed
that the
obtained material was 2-thiophenecarbonyl chloride with a purity of 97 area%.
1-1-1NMR
spectrum indicated the final product contained Bu20 in about 3% and aromatic
impurities of <
1%. 1-1-1-NMR (600 MHz, chloroform-d) 6 8.01 (dd, 1H, J = 4.0, 2.6 Hz), 7.85
(dd, 1H, J= 5.0,
1.3 Hz), 7.23 (dd, 1H, J= 5.0, 4.0 Hz).
Example 5: Alternative Preparation of 2-Thiophenecarbonyl Chloride From
Thiophene
(Sulfuric Acid Hydrolysis)
(1) add NCSAT slurry
CSI (1.15 eq.), Bu20
NõCl to 20% H2SO4
35 50 C S /S
C',1/ 0 (2) heat to reflux, 7
h
-
0
thiophene (thiophene-2-carbonyl)sulfamoyl chloride
(3)
(NCSAT separate layers;
)
extract aq. layer with
Bu20
(1) add DMF (cat.),
(30H SOCl2 (1.15 eq), 65 C
0
0
(2) distill product
2-thiophenecarbonyl chloride
2-thiophenecarboxylic acid directly from reaction
(TCA) mixture (TCC)
[0081] A solution of CSI (35.7 mL, 1.15 eq.) in dibutyl ether (50 mL) was
first heated to
40 C. A solution of thiophene (30 g, 0.36 mol) in dibutyl ether (10 mL) was
added dropwise via
a dropping funnel into the solution of CSI over 60 minutes. After addition of
about 60% of
thiophene, white precipitate was formed in the reaction mixture. After
completion of addition,
the resulting mixture was heated at 50 C for 2.5 hours. The resulting mixture
(the first mixture)
was taken directly for acid hydrolysis using aqueous sulfuric acid (20%).
[0082] Aqueous sulfuric acid (20%, 120 mL) in a round-bottom flask was cooled
with an
ice-bath while stirring. The aforementioned first mixture was slowly added
into the chilled
aqueous sulfuric acid, during which the internal temperature was kept below 50
C. After
completion of the addition, dibutyl ether (20 mL) was used to rinse the
remaining of the first
mixture and then added to the sulfuric mixture. The reaction mixture (the
second mixture) was
heated to reflux (¨ 110 C). After heating for 7 hours, the RP-HPLC showed that
2-
thiophenecarboxamide (TCAm), as the hydrolysis intermediate, was detected to
be < 3 area%.
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After being cooled to 70 C, the layers were separated. The aqueous layer was
extracted with hot
(70 C) dibutyl ether (2 x 20 mL), and the combined organic layers were washed
with water (1 x
15 mL) while the temperature of the organic layer was kept above 60 C. The
resulting mixture
of the organic layer (the third mixture) was taken directly for acyl chloride
formation with
thionyl chloride.
[0083] DMF (1.2 mL, 15 mmol) was added in a single portion to the
aforementioned
third mixture. Thionyl chloride (SOC12) (30 mL, 0.41 mol) was added dropwise
via a dropping
funnel to the reaction mixture that was preheated to 65 C. During the
addition, the released
sulfur dioxide (SO2) and hydrogen chloride (HC1) were captured with an aqueous
base trap. The
resulting mixture was heated at 65 C for additional 1 hour after completion of
the addition. The
reaction system was attached with a short path distillation head and a vigreux
column, and then
placed under a vacuum (300 to 30 mmHg). After removing gases in the reaction
mixture by
applying an initial vacuum (300 mmHg), the mixture was then heated to 100 C
under a vacuum
(30 mmHg). After dibutyl ether (¨ 60 mL) was distilled from the mixture, the
remaining mixture
was switched to a higher vacuum (5 mmHg). Distillation at a vapor temperature
of 50 - 60 C
(bath temperature was at ¨ 110 C) afforded 2-thiophenecarbonyl chloride as a
clear oil (34.0 g,
65%). GC-FID and 11-1NMR (600 MHz, chloroform-d) confirmed that the obtained
material was
2-thiophenecarbonyl chloride with a purity of 98 area%. lEINMR spectrum
indicated the final
product was free of dibutyl ether.
Example 6: Alternative Preparation of 2-Thiophenecarbonyl Chloride From
Thiophene
(Hydrochloride Acid Hydrolysis)
CSI (1.05 eq.), Bu20
/ \
N CI
(1) add water
-50 C S
______________________ yo- 0 0
(2) 6N HC1, heat to reflux, 7h
0
thiophene (thiophene-2-carbonyl)sulfamoyl chloride
(3)
(NCSAT) separate layers;
extract aq. layer with
Bu20
(1) add DMF (cat.),
IS \
ZL_OH SOC12 (1.15 eq), 65 C /S \ CI
0
0
(2) distill product
2-thiophenecarboxylic acid directly from reaction 2-
thiophenecarbonyl chloride
(TCC)
(TCA) mixture
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[0084] A solution of thiophene (50.0 g, 0.59 moles) in dibutyl ether (100 mL)
was
heated to 45-50 C. CSI (88.7 g, 0.63 moles, 1.05 eq.) was added dropwise via a
dropping funnel
into the solution of tiophene over 77 minutes. White precipitate was formed in
the reaction
mixture near the end of the addition and additional dibutyl ether (100 mL) was
added to
maintain the stirring of the slurry. The temperature was raised to 65 C to
complete the reaction.
At 7.8 hours, RP-HPLC analysis showed that only 1.3% of unreacted thiophene
remained. The
resulting mixture (the first mixture) was taken directly for acid hydrolysis
using aqueous
hydrochloride acid.
[0085] Water (50 g) was added slowly to moderate the strongly exothermic
hydrolysis
reaction, forming 2-thiophenecarboxamide. Aqueous HC1 solution (6N, 345.0 g,
1.88 moles
HC1) was added over 15 minutes, and the reaction mixture was heated to 100 C
for 7 hours to
convert the 2-thiophenecarboxamide to 2-thiophenecarboxylic acid. The layers
were separated
while hot and the aqueous phase was extracted with dibutyl ether (3 x 50 mL).
The empty
reaction vessel was rinsed with dibutyl ether (25 mL) to recover the remaining
2-
thiophenecarboxylic acid solids. The dibutyl ether layers were combined and
used directly for
acyl chloride formation with thionyl chloride.
[0086] The dibutyl ether mixture of 2-thiophenecarboxylic acid from above
(338.8 g),
along with DMF (1.92 g, 0.026 moles), was heated to 65 C. Thionyl chloride
(81.56 g, 0.68
moles) was added via a dropping funnel over one hour, during which there was a
steady
evolution of gas. The GC-FID showed that there was no remaining 2-
thiophenecarboxylic acid
after 1.5 hours. The dissolved gases and most of the dibutyl ether were
removed by distillation at
35-40 C under a vacuum (20 mmHg). The remaining dibutyl ether was removed
using a vacuum
pump. The product, 2-thiophene carbonyl chloride, was distilled at 47 C under
a vacuum (2
mmHg) as a colorless oil (56.20 g, 63.5%). GC-FID confirmed that the obtained
material was 2-
thiophenecarbonyl chloride with a purity of 98.4 area%.
EMBODIMENTS
[0087] For further illustration, additional non-limiting embodiments of the
present
disclosure are set forth below.
[0088] For example, embodiment 1 is a process for preparing 2-
thiophenecarbonyl
chloride, the process comprising:
reacting thiophene with chlorosulfonyl isocyanate in a reaction medium
comprising an
organic solvent, thereby producing (thiophene-2-carbonyl)sulfamoyl chloride,
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wherein the reaction is initiated by mixing the thiophene and the
chlorosulfonyl
isocyanate,
and wherein the chlorosulfonyl isocyanate is present in molar excess relative
to
thiophene.
[0089] Embodiment 2 is the process of embodiment 1 wherein the organic solvent
comprises a compound selected from the group consisting of Ci-Cio alkane
solvents, Ci-Cio
halogenated alkane solvents, C1-C10 alkylbenzenes, halogenated aromatic
solvents, and dialkyl
ether solvents of the general formula R¨O¨R', wherein R and R' are each
independently selected
from Ci-C6 alkyl.
[0090] Embodiment 3 is the process of embodiment 1 wherein the organic solvent
comprises a compound of the formula R¨O¨R' wherein R is selected from C4-C6
cycloalkyl and
R' is methyl.
[0091] Embodiment 4 is the process of embodiment 1 wherein the organic solvent
comprises cyclopentyl methyl ether.
[0092] Embodiment 5 is the process of embodiment 1 wherein the organic solvent
comprises a compound of the formula R¨O¨R' wherein R and R' are each C3-C6
alkyl.
[0093] Embodiment 6 is the process of embodiment 1 wherein the organic solvent
comprises dibutyl ether.
[0094] Embodiment 7 is a process for preparing 2-thiophenecarbonyl chloride,
the
process comprising:
reacting thiophene with chlorosulfonyl isocyanate in a reaction medium
comprising an
organic solvent, thereby producing (thiophene-2-carbonyl)sulfamoyl chloride,
wherein the organic solvent comprises dibutyl ether.
[0095] Embodiment 8 is the process of any one of embodiments 1 to 7 wherein
the
reaction is initiated by adding the thiophene to the chlorosulfonyl
isocyanate, and wherein the
chlorosulfonyl isocyanate is present in molar excess relative to the
thiophene.
[0096] Embodiment 9 is the process of any one of embodiments 1 to 7 wherein
the
reaction is initiated by adding the chlorosulfonyl isocyanate to the
thiophene, and wherein the
chlorosulfonyl isocyanate is present in molar excess relative to the
thiophene.
[0097] Embodiment 10 is the process of any one of embodiments 1 to 9 wherein
the
molar ratio of chlorosulfonyl isocyanate to thiophene is from about 1.05:1 to
about 1.5:1, from
about 1.05:1 to about 1.25:1, from about 1.05:1 to about 1.2:1, from about
1.05:1 to about
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1.15:1, from about 1.1:1 to about 1.5:1, from about 1.1:1 to about 1.25:1,
from about 1.1:1 to
about 1.2:1, or from about 1.1:1 to about 1.15:1.
[0098] Embodiment 11 is the process of any one of embodiments 1 to 10 wherein
the
(thiophene-2-carbonyl)sulfamoyl chloride is maintained as a substantially
homogenous solution
in a liquid organic phase comprising the organic solvent.
[0099] Embodiment 12 is the process of any one of embodiments 1 to 11 wherein
the
(thiophene-2-carbonyl)sulfamoyl chloride is maintained as a solid suspension
in a liquid organic
phase comprising the organic solvent.
[00100] Embodiment 13 is the process of any one of embodiments 1 to 12 wherein
the
(thiophene-2-carbonyl)sulfamoyl chloride is isolated as a solid by filtration,
centrifugation,
and/or decantation.
[00101] Embodiment 14 is the process of any one of embodiments 1 to 13 wherein
the
reaction is carried out at a temperature of from about -20 C to about 100 C,
from about 0 C to
about 50 C, or from about 35 C to about 50 C.
[00102] Embodiment 15 is the process of any one of embodiments 1 to 14 further
comprising a hydrolysis reaction step in which (thiophene-2-carbonyl)sulfamoyl
chloride is
hydrolyzed to produce 2-thiophenecarboxylic acid.
[00103] Embodiment 16 is the process of embodiment 15 wherein the hydrolysis
reaction
is initiated by adding (thiophene-2-carbonyl)sulfamoyl chloride to an aqueous
medium
comprising a strong acid,
wherein the (thiophene-2-carbonyl)sulfamoyl chloride is present in the form of
a
substantially homogenous solution, in the form of an isolated solid, or in the
form of a solid
suspension in a liquid organic phase comprising the organic solvent.
[00104] Embodiment 17 is the process of embodiment 16 wherein the (thiophene-2-
carbonyl)sulfamoyl chloride is present in the form of a substantially
homogenous solution in a
liquid organic phase comprising the organic solvent.
[00105] Embodiment 18 is the process of embodiment 16 wherein the (thiophene-2-
carbonyl)sulfamoyl chloride is present in the form of an isolated solid.
[00106] Embodiment 19 is the process of embodiment 16 wherein the (thiophene-2-
carbonyl)sulfamoyl chloride is present in the form of a solid suspension in a
liquid organic phase
comprising the organic solvent.
[00107] Embodiment 20 is the process of embodiment 16 wherein the strong acid
comprises a compound selected form the group consisting of hydrochloric acid
and sulfuric acid.
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[00108] Embodiment 21 is the process of embodiment 20 wherein the strong acid
comprises hydrochloric acid.
[00109] Embodiment 22 is the process of embodiment 21 wherein the hydrochloric
acid
has a concentration of from about 1 M to about 12 M, or from about 3 wt% to
about 37 wt%.
[00110] Embodiment 23 is the process of embodiment 20 wherein the strong acid
comprises sulfuric acid.
[00111] Embodiment 24 is the process of embodiment 23 wherein the sulfuric
acid has a
concentration of from about 1 M to about 18 M, or from 5 wt% to about 95 wt%.
[00112] Embodiment 25 is the process of any one of embodiments 16 to 24
wherein an
organic solvent is added to the medium comprising the (thiophene-2-
carbonyl)sulfamoyl
chloride and the strong acid to form an acidic reaction medium.
[00113] Embodiment 26 is the process of embodiment 25 wherein the organic
solvent
comprises dibutyl ether.
[00114] Embodiment 27 is the process of any one of embodiments 16 to 26
wherein the
volumetric ratio of the organic solvent and the acid aqueous medium is from
about 1:4 to about
1:1, from about 1:2 to about 1:1, from about 2:3 to about 1:1, or from about
3:4 to about 1:1.
[00115] Embodiment 28 is the process of any one of embodiments 25 to 27
wherein the
acidic reaction medium is heated at a temperature of at least about 80 C.
[00116] Embodiment 29 is the process of embodiment 28 wherein the temperature
of the
acidic reaction medium is maintained from about 50 C to about 130 C, or from
about 70 C to
about 115 C during the hydrolysis step.
[00117] Embodiment 30 is the process of embodiment 15 wherein the hydrolysis
reaction
is initiated by adding (thiophene-2-carbonyl)sulfamoyl chloride to a basic
medium comprising a
strong base,
wherein the (thiophene-2-carbonyl)sulfamoyl chloride is present in the form of
a
substantially homogenous solution, in the form of an isolated solid, or in the
form of a solid
suspension in a liquid organic phase comprising the organic solvent.
[00118] Embodiment 31 is the process of embodiment 30 wherein the strong base
comprises a compound selected form the group consisting of sodium hydroxide
and potassium
hydroxide.
[00119] Embodiment 32 is the process of embodiment 31 wherein the strong base
comprises sodium hydroxide.
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[00120] Embodiment 33 is the process of embodiment 32 wherein the sodium
hydroxide
has a concentration of from about 1 M to about 20 M, or from about 2.5 wt% to
about 50 wt%.
[00121] Embodiment 34 is the process of embodiment 31 wherein the strong acid
comprises potassium hydroxide.
[00122] Embodiment 35 is the process of embodiment 34 wherein the potassium
hydroxide has a concentration of from about 1 M to about 12 M, or from 4 wt%
to about 45
wt%.
[00123] Embodiment 36 is the process of embodiment 30 further comprising a
neutralization step in which a salt form of 2-thiophenecarboxylic acid from
the base hydrolysis
is neutralized with an acid to the 2-thiophenecarboxylic acid.
[00124] Embodiment 37 is the process of any one of embodiments 16 to 36
wherein the
reaction medium is allowed to separate into an aqueous phase and an organic
phase comprising
2-thiophenecarboxylic acid,
and wherein the organic phase comprising 2-thiophenecarboxylic acid is
separated from
the aqueous phase.
[00125] Embodiment 38 is the process of embodiment 37 wherein the organic
phase
comprising 2-thiophenecarboxylic acid is separated from the aqueous phase
using decantation.
[00126] Embodiment 39 is the process of embodiment 38 wherein the organic
phase is
maintained at a temperature of at least about 60 C or at least about 70 C
during the decantation
step.
[00127] Embodiment 40 is the process of any one of embodiments 1 to 39 further
comprising a chlorination step in which 2-thiophenecarboxylic acid dissolved
in the organic
solvent is reacted with a chlorinating agent to produce 2-thiophenecarbonyl
chloride in a liquid
medium.
[00128] Embodiment 41 is the process of embodiment 40 wherein the chlorinating
agent
comprises thionyl chloride.
[00129] Embodiment 42 is the process of embodiment 41 wherein the chlorination
reaction is initiated by adding a first liquid medium comprising thionyl
chloride to a second
liquid medium comprising 2-thiophenecarboxylic acid,
wherein the second liquid medium comprises 2-thiophenecarboxylic acid
dissolved in
the organic solvent.
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[00130] Embodiment 43 is the process of embodiment 42 wherein the chlorination
reaction is carried out in the presence of a catalyst that promotes formation
of 2-
thiophenecarbonyl chloride.
[00131] Embodiment 44 is the process of embodiment 43 wherein the catalyst
comprises
dimethylformamide.
[00132] Embodiment 45 is the process of embodiment 44 wherein the molar
percentage
of N,N-dimethylformamide to 2-thiophenecarboxylic acid is from about 1 mol% to
about 5
mol%.
[00133] Embodiment 46 is the process of any one of embodiments 42 to 45
wherein the
chlorination reaction is carried out with the thionyl chloride present in
molar excess relative to
2-thiophenecarboxylic acid.
[00134] Embodiment 47 is the process of embodiment 46 wherein the molar ratio
of
thionyl chloride to 2-thiophenecarboxylic acid is from about 1:1 to about 2:1,
from about 1.5:1
to about 2:1, from about 1.1:1 to about 1.5:1, or from about 1.1:1 to about
1.25:1.
[00135] Embodiment 48 is the process of any one of embodiments 42 to 47
wherein the
chlorination reaction is carried out at a temperature of from about 50 C to
about 80 C, or from
about 60 C to about 70 C.
[00136] Embodiment 49 is the process of any one of embodiments 1 to 48 further
comprising a distillation step in which 2-thiophenecarbonyl chloride is
recovered by distillation
of the liquid medium.
[00137] Embodiment 50 is the process of embodiment 49 wherein the distillation
comprises a solvent removal step.
[00138] Embodiment 51 is a process for preparing 2-thiophenecarbonyl chloride,
the
process comprising:
mixing a first liquid medium comprising thiophene dissolved in dibutyl ether
and a
second liquid medium comprising chlorosulfonyl isocyanate, thereby producing a
third liquid
medium comprising (thiophene-2-carbonyl)sulfamoyl chloride in the form of a
substantially
homogeneous solution or a solid suspension in a liquid organic phase
comprising dibutyl ether,
wherein the chlorosulfonyl isocyanate is present in the second liquid medium
in molar excess
relative to thiophene in the first liquid medium;
adding at least a portion of the third liquid medium to an aqueous medium
comprising
hydrochloric acid or sulfuric acid, thereby producing a fourth liquid medium
comprising 2-
thiophenecarboxylic acid dissolved in an organic phase comprising dibutyl
ether; and
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reacting at least a portion of the 2-thiophenecarboxylic acid present in the
fourth liquid
medium with thionyl chloride, thereby producing a reaction medium comprising 2-
thiophenecarbonyl chloride.
[00139] Embodiment 52 is a process for preparing 2-thiophenecarbonyl chloride,
the
process comprising:
mixing a first liquid medium comprising thiophene dissolved in dibutyl ether
and a
second liquid medium comprising chlorosulfonyl isocyanate, thereby producing a
third liquid
medium comprising (thiophene-2-carbonyl)sulfamoyl chloride in the form of a
substantially
homogeneous solution or a solid suspension in a liquid organic phase
comprising dibutyl ether,
wherein the chlorosulfonyl isocyanate is present in the second liquid medium
in molar excess
relative to thiophene in the first liquid medium;
adding at least a portion of the third liquid medium to an aqueous medium
comprising
sodium hydroxide or potassium hydroxide, thereby producing a fourth liquid
medium
comprising a salt form of 2-thiophenecarboxylic acid in an organic phase
comprising dibutyl
ether; neutralizing at least a portion of the fourth liquid medium to a fifth
liquid medium
comprising 2-thiophenecarboxylic acid dissolved in an organic phase comprising
dibutyl ether;
and
reacting at least a portion of the 2-thiophenecarboxylic acid present in the
fifth liquid
medium with thionyl chloride, thereby producing a reaction medium comprising 2-
thiophenecarbonyl chloride.
[00140] Embodiment 53 is a process for preparing 2-thiophenecarbonyl chloride,
the
process comprising:
mixing a first liquid medium comprising thiophene dissolved in dibutyl ether
and a
second liquid medium comprising chlorosulfonyl isocyanate, thereby producing a
third liquid
medium comprising (thiophene-2-carbonyl)sulfamoyl chloride in the form of a
substantially
homogeneous solution or a solid suspension in a liquid organic phase
comprising dibutyl ether,
wherein the chlorosulfonyl isocyanate is present in the second liquid medium
in molar excess
relative to thiophene in the first liquid medium;
adding at least a portion of the third liquid medium to an aqueous medium
comprising
water, thereby producing a fourth liquid medium comprising 2-
thiophenecarboxamide;
contacting at least a portion of the forth liquid medium in the presence of a
strong acid or a
strong base, thereby producing a fifth liquid medium of 2-thiophenecarboxylic
acid in an
organic phase comprising dibutyl ether; and
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reacting at least a portion of the 2-thiophenecarboxylic acid present in the
fifth liquid
medium with thionyl chloride, thereby producing a reaction medium comprising 2-
thiophenecarbonyl chloride.
[00141] Embodiment 54 is the process of any one of embodiments 51 to 53
wherein the
reaction is initiated by adding the first liquid medium comprising thiophene
to the second liquid
medium comprising chlorosulfonyl isocyanate.
[00142] Embodiment 55 is the process of any one of embodiments 51 to 53
wherein the
reaction is initiated by adding the second liquid medium comprising
chlorosulfonyl isocyanate
to the first liquid medium comprising thiophene.
[00143] Embodiment 56 is a process for preparing a 3,5-disubstituted 1,2,4-
oxadiazole of
Formula (I) or a salt thereof,
0
Ar2
Arl
(I)
wherein Ari is selected from the group consisting of phenyl, pyridyl, pyrazyl,
oxazolyl or
isoxazolyl, each of which can be optionally independently substituted with one
or more
substituents selected from the group consisting of halogen, CF3, CH3, OCF3,
OCH3, CN and
C(H)0, and Ar2 is thienyl, which can be optionally independently substituted
with one or more
substituents selected from the group consisting of fluorine, chlorine, CH3,
and OCF3,
the process comprising reacting an N-hydroxyamidine of Formula (II), or a
tautomeric
form thereof,
Arl NH
HN
OH
(II)
with 2-thiophenecarbonyl chloride that is prepared by a process as set forth
in any one of
embodiments 1 to 55.
[00144] Embodiment 57 is a process for preparing a 3,5-disubstituted 1,2,4-
oxadiazole of
Formula (I) or a salt thereof,
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0
Ari
(I)
the process comprising adding a first liquid medium comprising thiophene
dissolved in
dibutyl ether to a second liquid medium comprising chlorosulfonyl isocyanate,
thereby
producing a third liquid medium comprising (thiophene-2-carbonyl)sulfamoyl
chloride in the
form of a substantially homogeneous solution or a solid suspension in a liquid
organic phase
comprising dibutyl ether, wherein the chlorosulfonyl isocyanate is present in
the second liquid
medium in molar excess relative to thiophene in the first liquid medium;
adding at least a portion of the third liquid medium to an aqueous medium
comprising a
strong acid or a strong base, thereby producing a fourth liquid medium
comprising 2-
thiophenecarboxylic acid dissolved in an organic phase comprising dibutyl
ether;reacting at least
a portion of the 2-thiophenecarboxylic acid present in the fourth liquid
medium with thionyl
chloride, thereby producing a reaction medium comprising 2-thiophenecarbonyl
chloride;
and reacting at least a portion of the 2-thiophenecarbonyl chloride obtained
in the fourth
liquid reaction medium with an N-hydroxyamidine of Formula (II), or a
tautomeric form
thereof,
Ari NH
HN
OH
(II)
wherein Ari is selected from the group consisting of phenyl, pyridyl, pyrazyl,
oxazolyl or
isoxazolyl, each of which can be optionally independently substituted with one
or more
substituents selected from the group consisting of halogen, CF3, CH3, OCF3,
OCH3, CN and
C(H)0, and Ar2 is thienyl, which can be optionally independently substituted
with one or more
substituents selected from the group consisting of fluorine, chlorine, CH3,
and OCF3.
[00145] Embodiment 58 is the process of embodiment 56 or 57 wherein the 3,5-
disubstituted-1,2,4-oxadiazole of Formula (I) is 3-pheny1-5-(2-thieny1)-1,2,4-
oxadiazole, or a
salt thereof.
[00146] When introducing elements of the present disclosure or the preferred
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embodiments(s) thereof, the articles "a", "an", "the" and "said" are intended
to mean that there
are one or more of the elements. The terms "comprising", "including" and
"having" are intended
to be inclusive and mean that there may be additional elements other than the
listed elements.
[00147] In view of the above, it will be seen that the several objects of the
disclosure are
achieved and other advantageous results attained.
[00148] As various changes could be made in the above products and methods
without
departing from the scope of the disclosure, it is intended that all matter
contained in the above
description shall be interpreted as illustrative and not in a limiting sense.
